The objective of this proposal is to establish evidence of increased stimulation of the pituitary-adrenal (HPA) axis by the hypothalamic peptide, corticotropin releasing hormone (CRH), in major depressive disorder (MDD). This aim will be pursued by testing the following hypotheses: 1. The ACTH secretory responses to exogenous ovine CRH (oCRH) stimulation and to stimulation by endogenous CRH released from the hypothalamus during a physiologic stress, insulin-induced hypoglycemia (IH), will be decreased in patients with MDD compared with normal control subjects (CRH receptordownregulation). 2. The ACTH secretory response to exogenous arginine-vasopressin (AVP) stimulation will not be similarly decreased and may be increased in MDD patients compared with normal controls (increased corticotroph ACTH secretory capacity and potentiation of AVP by increased endogenous CRH stimulation of ACTH secretion). 3. The ratio of the cortisol secretory response to the log transformed ACTH secretory response (cortisol/log ACTH secretory ratio) will be increased during stimulation with all three neuroendocrine stimuli (oCRH, AVP, IH) in MDD patients compared with normal controls (increased adrenal cortex sensitivity to ACTH). 4. Levels of CRH-immunoreactivity (CRH-IR) in the cerebrospinal fluid (CSF) will be increased in MDD patients compared with normal controls (increased secretion of endogenous CRH) and will be correlated with decreases in the ACTH secretory response and with increases in the cortisol/log ACTH secretory ratio during stimulation with exogenous oCRH in MDD patients. To test these hypotheses, plasma ACTH and cortisol levels will be determined during a series of three stimulation tests (oCRH, AVP, IH) and a 1 mg dexamethasone suppression test (DST) will be performed in 60 patients with MDD and in 30 age- and sex-matched normal controls. CSF levels of endogenous CRH-IR, AVP-IR, and somatostatin-IR will be determined and compared with the ACTH and cortisol secretory response to oCRH and with DST results in additional groups of 40 patients with MDD and 30 age- and sex-matched normal controls. The results of this study will be of significance in further defining the neuroendocrine pathophysiology responsible for increased secretion of ACTH and cortisol in MDD by determining if there is evidence of increased CRH secretion and increased CRH stimulation of the PA axis. The study could have major implications for the understanding of abnormalities in hypothalamic peptide function which occur during episodes of MDD.